Insulinotropic polypeptides have insulinotropic activity, i.e., have the ability to stimulate, or to cause the stimulation of, the synthesis or expression of the hormone insulin. Insulinotropic peptides include, but are not limited to, GLP-1, exendin-3, exendin-4, and precursors, derivatives, or fragments thereof.
Pro-glucagon-derived peptides, including glucagon and glucagon-like peptide-1 (GLP-1), are found in many metabolic pathways involved in different physiological functions, such as insulin secretion and regulation of food intake.
Pre-pro-glucagon is a 158 amino acid polypeptide that is processed to a number of different active compounds. GLP-1, e.g., corresponds to amino acid residues 72 through 108 of pre-pro-glucagon. GLP-1 among other functions results in the stimulation of insulin synthesis and secretion and inhibition of food intake. GLP-1 has been shown to reduce hyperglycemia (elevated glucose levels) in diabetics.
Glucose-dependent insulinotropic peptide (GIP) is a 42-amino acid gastrointestinal regulatory peptide that stimulates insulin secretion from pancreatic beta cells in the presence of glucose. It is derived by proteolytic processing from a 133-amino acid precursor, pre-pro-GIP.
In WO 2010/011439 GIP-based mixed agonists for treatment of metabolic disorders and obesity are reported. It is reported that modifications to the native glucagon sequence produce glucagon peptides that can exhibit potent glucagon activity equivalent to or better than the activity of native glucagon, potent GIP activity equivalent to or better than the activity of native GIP, and/or potent GLP-1 activity equivalent to or better than the activity of native GLP-1. The data provided is reported to show that peptides having both GIP activity and GLP-1 activity are particularly advantageous for inducing weight loss or preventing weight gain, as well as for treating hyperglycemia, including diabetes, whereby the combination of GIP agonist activity with GLP-1 agonist activity produces a greater effect on weight reduction than GLP-1 alone.
The conjugation of insulinotropic polypeptides to antibodies or antibody fragments is hypothetically outlined in e.g. WO 2010/011439, U.S. Pat. No. 6,329,336 and U.S. Pat. No. 7,153,825.
Discovery of dual-action membrane-anchored modulators of incretin receptors is reported by Fortin, J-P., et al. (PlosOne 6 (2011) e24693). Finan, B., et al., report that unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans (Sci. Transl. Med. 5 (2013) 209ra151).